RT Journal Article
SR Electronic
T1 Genetically engineered pigs manifesting pancreatic agenesis with severe diabetes
JF BMJ Open Diabetes Research & Care
JO BMJ Open Diab Res Care
FD American Diabetes Association
SP e001792
DO 10.1136/bmjdrc-2020-001792
VO 8
IS 2
A1 Masaki Nagaya
A1 Koki Hasegawa
A1 Masahito Watanabe
A1 Kazuaki Nakano
A1 Kazutoshi Okamoto
A1 Takeshi Yamada
A1 Ayuko Uchikura
A1 Kenji Osafune
A1 Harumasa Yokota
A1 Taiji Nagaoka
A1 Hitomi Matsunari
A1 Kazuhiro Umeyama
A1 Eiji Kobayashi
A1 Hiromitsu Nakauchi
A1 Hiroshi Nagashima
YR 2020
UL http://drc.bmj.com/content/8/2/e001792.abstract
AB Introduction Pancreatic duodenum homeobox 1 (Pdx1) expression is crucial for pancreatic organogenesis and is a key regulator of insulin gene expression. Hairy and enhancer of split 1 (Hes1) controls tissue morphogenesis by maintaining undifferentiated cells. Hes1 encodes a basic helix loop helix (bHLH) transcriptional repressor and functionally antagonizes positive bHLH genes, such as the endocrine determination gene neurogenin-3. Here, we generated a new pig model for diabetes by genetic engineering Pdx1 and Hes1 genes.Research design and methods A transgenic (Tg) chimera pig with germ cells carrying a construct expressing Hes1 under the control of the Pdx1 promoter was used to mate with wild-type gilts to obtain Tg piglets.Results The Tg pigs showed perinatal death; however, this phenotype could be rescued by insulin treatment. The duodenal and splenic lobes of the Tg pigs were slender and did not fully develop, whereas the connective lobe was absent. β cells were not detected, even in the adult pancreas, although other endocrine cells were detected, and exocrine cells functioned normally. The pigs showed no irregularities in any organs, except diabetes-associated pathological alterations, such as retinopathy and renal damage.Conclusion Pdx1-Hes1 Tg pigs were an attractive model for the analysis of pancreatic development and testing of novel treatment strategies for diabetes.